Aduhelm vs. Exondys-51: Understanding the disparity in launch success of two similarly uncertain evidence packages
In June, Windrose’s Elizaveta Tchebaniouk provided an analysis of Aduhelm’s approval in Alzheimer’s Disease (AD) and the dynamic environment surrounding Biogen’s launch in the US. High unmet need, uncertain evidence, modest clinical benefit, and affordability concerns continue to make for a highly complex commercial launch. [1]
Since the time of publishing our original article, commercial challenges have continued to make things difficult for Biogen. Several large hospital networks, such as Mt. Sinai and the Cleveland Clinic, have chosen not to prescribe Aduhelm, while a major neurology clinic in Washington D.C. has decided to ban Biogen representatives from entering their premises. [2], [3] Many national and regional US payers have also implemented policies to not cover Aduhelm until further guidance comes from CMS’ ongoing National Coverage Determination (NCD). Additionally, 3 independent FDA Advisory Committee members even resigned in the wake of the controversial approval. [4]
While the fallout from this FDA decision remains in the public eye, it’s certainly not the first time a product has been approved with uncertain evidence and concerns around value. In fact, Aduhelm’s ensuing controversy has in many ways paralleled the contentious 2016 approval of Exondys-51. However, while both products received pushback from the scientific communities around their uncertain clinical benefit, they had vastly different post-approval and commercialization outcomes. In this article, we identify the key differences between these launches, which may be responsible for the contrasting commercial outcomes immediately post-launch.
Exondys-51 is indicated for Duchenne Muscular Dystrophy (DMD), a severe genetic disease that primarily affects young boys and is characterized by progressive muscle degeneration. Despite the urgent need for an effective DMD therapy, most of the FDA scientific staff opposed approval of Exondys-51 due to the use of disputed surrogate endpoints and lack of clear data thresholds or predictive value.[5] Nonetheless, strong DMD patient advocacy and ensuing political pressure led, in part, to an eventual approval. Exondys-51 was subsequently covered by a majority of US plans and uptake was strong.[6][7][8]
So why the disparity in launch success?
When examining both Aduhelm and Exondys-51, we can see several key similarities. Both products target patients with high unmet need and active advocacy communities. Additionally, both achieved approval in an area fraught with recent FDA rejections, utilized unvalidated surrogate endpoints with questionable predictive value, and demonstrated modest benefit on key efficacy endpoints. Lastly, Exondys-51 and Aduhelm had negative FDA advisory committee decisions reversed.
However, there are several key differences between these two which led to very different commercial journeys immediately post-approval:
Patient type: Exondys-51 targets a pediatric population with rapid progression in which young boys are wheelchair bound and have an average life expectancy in the early 20s. While Aduhelm also targets a population with high unmet need it affects older patients on average. [9]
Population size: Exondys-51 targets DMD, with a prevalence of a few thousand patients, while Biogen predicts that Aduhelm could be an option for 1-2 million patients with mild dementia. [10]
Safety issues: Aduhelm (and other previously failed amyloid-targeting antibodies) are highly linked to Amyloid-Related Imaging Abnormality (ARIA), a form of brain swelling and bleeding with unknown long-term impact on cognitive decline. Exondys-51 was not met with any notable safety concerns.
Clinician support: Prior to the FDA Advisory Committee Meeting for Exondys-51, 36 Medical Experts wrote an open letter urging the FDA for approval. Despite patient demand for Aduhelm, the medical community has been much more resistant to uptake. [12][13]
Comparison of Key Attributes: Exondys-51 vs. Aduhelm
Key Similarities and Differences between Exondys-51 and Aduhelm Before and After Accelerated Approval
Windrose’s take
Windrose frequently supports clients in exploring the opportunities and challenges facing products with uncertain evidence packages. While Aduhelm and Exondys-51 may be unique cases, we do feel there are several key considerations which can be applied to all products launching with surrogate evidence and/or Accelerated Approval:
While unmet need may create demand for new therapies and support the Accelerated Approval of new entrants, it is not a standalone guarantee of access and commercial success
Still, in areas of high unmet need there is greater acceptance by Healthcare Professionals (HCPs) and payers of surrogate endpoints, despite limited predictive value and no clear thresholds for demonstrating benefit
However, these endpoints must have strong clinician support for payers to consider immediate and/or broad coverage, particularly in larger patient populations
Finally, safety issues will negatively impact willingness to accept uncertain surrogate evidence across stakeholders – again, this is particularly true in larger populations
It is also critical to monitor how the relationship between payers, clinicians, and the FDA continues to evolve as the Aduhelm launch takes shape – the days of de facto reimbursement in high unmet need areas may be waning. Dr. Aaron Kesselheim, one of the 3 FDA advisory panel members who resigned in June, went as far as to say “this [approval of Aduhelm] will undermine the care of these patients, public trust in the FDA, the pursuit of useful therapeutic innovation, and the affordability of the healthcare system” [14]
Jonathan Xue, Analyst, Windrose Consulting Group (Primary Author)
Colin Nash, Senior Principal, Windrose Consulting Group (secondary author)